We have assembled a complementary team of basic B-cell scientists, lymphoma biologists, immunologists, hematopathologists, genomics and bioinformatics specialists, clinical investigators and biostatisticians to delineate the critical events in the pathogenesis and pathophysiology of the most common adult lymphoid malignancies and germinal center (GC) B-cell lymphomas, follicular lymphoma (FL) and diffuse large B-cell lymphomas (DLBCL). Although the treatment options for these diseases have expanded in recent years, FL is still incurable and DLBCL is cured in less than 50 percent of patients. It is our belief that the proposed studies will identify rational targets for more effective and specific treatment of these diseases in the funding period. This new P01 application is based upon the following hypothesis: 1) errors in immunoglobulin gene rearrangement predispose to the development of GC B-cell lymphomas; 2) dysregulated expression of genes controlling apoptosis (bcl-2) or normal GC development (bcl-6) also contribute to the pathogenesis of these diseases; 3) biologically-discrete subsets of GC B-cell lymphomas with unique natural histories remain to be defined; and 4) host immune responses influence outcome in GC B-cell lymphomas. Drs. F. Alt and K. Rajewsky will evaluate molecular mechanisms of translocations in GC B-cell lymphomas (Project 1). Dr. S. Korsmeyer will assess apoptosis as a molecular target in the genesis and maintenance of B-cell lymphoma (Project 2) and Dr. Dalla-Favera will evaluate the role of bcl-6 in GC formation and lymphomagenesis (Project 3). Dr. M. Shipp will delineate molecular signatures of outcome in GC B-cell lymphomas (Project 4) and Drs. L. Nadler, A. Freedman, and J. Schultze will analyze T-cell immunity in GC B-cell lymphomas. Cores which support the proposed studies include: DNA Microarray/Bioinformatics (T. Golub); Hematopathology (J. Aster); Clinical Trials (J. Gribben); Biostatistics (D. Neuberg); and Administration (M. Shipp).